ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.278_279delinsTT (p.Gly93Val)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000551.4(VHL):c.278_279delinsTT (p.Gly93Val)
Variation ID: 583075 Accession: VCV000583075.8
- Type and length
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Indel, 2 bp
- Location
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Cytogenetic: 3p25.3 3: 10142125-10142126 (GRCh38) [ NCBI UCSC ] 3: 10183809-10183810 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 10, 2018 Feb 28, 2024 Nov 14, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000551.4:c.278_279delinsTT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Gly93Val missense NM_000551.3:c.278_279delGCinsTT NM_001354723.2:c.278_279delinsTT NP_001341652.1:p.Gly93Val missense NM_198156.3:c.278_279delinsTT NP_937799.1:p.Gly93Val missense NC_000003.12:g.10142125_10142126delinsTT NC_000003.11:g.10183809_10183810delinsTT NG_008212.3:g.5491_5492delinsTT LRG_322:g.5491_5492delinsTT - Protein change
- G93V
- Other names
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- Canonical SPDI
- NC_000003.12:10142124:GC:TT
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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VHL | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
790 | 1943 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (1) |
criteria provided, single submitter
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Nov 14, 2020 | RCV000707314.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 18, 2020 | RCV001016587.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Jun 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001177553.3
First in ClinVar: Mar 16, 2020 Last updated: Nov 29, 2022 |
Comment:
The c.278_279delGCinsTT variant (also known as p.G93V), located in coding exon 1 of the VHL gene, results from an in-frame deletion of GC and insertion … (more)
The c.278_279delGCinsTT variant (also known as p.G93V), located in coding exon 1 of the VHL gene, results from an in-frame deletion of GC and insertion of TT at nucleotide positions 278 to 279. This results in the substitution of the glycine residue for a valine residue at codon 93, an amino acid with dissimilar properties. An variant resulting in the same amino acid substitution, p.G93V (c.278G>T), has been reported in a cohort of patients with non-syndromic pheochromocytoma (Neumann HP et al. N. Engl. J. Med., 2002 May;346:1459-66). Further, other missense variants at this codon (p.G93D, p.G93S, p.G93R, p.G93C) have been reported in numerous individuals with personal and/or family history consistent with Von Hippel-Lindau syndrome (VHL) (Chen F et al. Hum. Mutat., 1995;5:66-75; Zbar B et al. Hum. Mutat., 1996;8:348-57; Glavac D et al. Hum. Genet., 1996 Sep;98:271-80; Neumann HP et al. N. Engl. J. Med., 2002 May;346:1459-66; Klein B et al. Hum. Genet., 2001 May;108:376-84; Schreinemakers JM et al. World J Surg Oncol, 2007 Oct;5:112; Iacobone M et al. Surgery, 2011 Dec;150:1194-201). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Nov 14, 2020)
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criteria provided, single submitter
Method: clinical testing
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Von Hippel-Lindau syndrome
Chuvash polycythemia
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000836405.3
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
A different missense substitution at this codon (p.Gly93Ser) has been determined to be pathogenic (PMID: 11409863, 12000816, 8707293, 22136840, 17922902). This suggests that the glycine … (more)
A different missense substitution at this codon (p.Gly93Ser) has been determined to be pathogenic (PMID: 11409863, 12000816, 8707293, 22136840, 17922902). This suggests that the glycine residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with clinical features of von Hippel-Lindau syndrome (PMID: 10095351, 12000816, Invitae, external communication). ClinVar contains an entry for this variant (Variation ID: 583075). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 93 of the VHL protein (p.Gly93Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Is genetic screening indicated in apparently sporadic pheochromocytomas and paragangliomas? | Iacobone M | Surgery | 2011 | PMID: 22136840 |
Genetic analysis of von Hippel-Lindau disease. | Nordstrom-O'Brien M | Human mutation | 2010 | PMID: 20151405 |
A patient with bilateral pheochromocytoma as part of a Von Hippel-Lindau (VHL) syndrome type 2C. | Schreinemakers JM | World journal of surgical oncology | 2007 | PMID: 17922902 |
Germ-line mutations in nonsyndromic pheochromocytoma. | Neumann HP | The New England journal of medicine | 2002 | PMID: 12000816 |
DHPLC-based germline mutation screening in the analysis of the VHL tumor suppressor gene: usefulness and limitations. | Klein B | Human genetics | 2001 | PMID: 11409863 |
[Retinal capillary angioma. Clinical and molecular genetic studies]. | Kreusel KM | Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft | 1999 | PMID: 10095351 |
Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. | Zbar B | Human mutation | 1996 | PMID: 8956040 |
Mutations in the VHL tumor suppressor gene and associated lesions in families with von Hippel-Lindau disease from central Europe. | Glavac D | Human genetics | 1996 | PMID: 8707293 |
Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. | Chen F | Human mutation | 1995 | PMID: 7728151 |
Text-mined citations for rs1559426072 ...
HelpRecord last updated Mar 05, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.